Mori Yukio, Tatematsu Kenjiro, Koide Akihiro, Sugie Shigeyuki, Tanaka Takuji, Mori Hideki
Institute of Biological Pharmacy, Gifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, Japan.
Cancer Sci. 2006 Sep;97(9):896-904. doi: 10.1111/j.1349-7006.2006.00261.x. Epub 2006 Jun 29.
To elucidate the mechanism underlying suppression by curcumin of esophageal carcinogenesis induced by NMBA, we evaluated the CYP level and mutagenic activation of environmental carcinogens, by immunoblot analyses and Ames preincubation test, respectively, and bilirubin, 4-nitrophenol and testosterone UDPGT activities in F344 rats treated with curcumin and/or NMBA. No significant alterations in the hepatic levels of constitutive CYP proteins, mutagenic activation by liver S9 or hepatic UDPGT activities were produced by subcutaneous treatment with 0.5 mg/kg NMBA for 5 weeks and/or feeding of 0.05% and 0.2% curcumin for 6 weeks. In contrast, gavage of 0.2% curcumin decreased esophageal CYP2B1 and 2E1 by up to 60%, compared with vehicle control. Similarly, intragastric treatment with 270 mg/kg curcumin decreased esophageal and gastric CYP2B1 and CYP2E1, but not in lung, kidney or intestine. Conversely, large intestinal CYP2B1 was 2.8-fold higher in the treated rats than in control rats. Mutagenic activities of NOC, including NMBA, in the presence of esophagus and stomach S9 were markedly decreased in the treated rats, whereas those in the presence of large intestine S9 were 2.2-3.0-fold above control. These results show that modifying effects of curcumin on esophageal carcinogenesis can be attributed to a decrease in metabolic activation of NMBA by esophageal CYP2B1 during the initiation phase, without the contribution of metabolic activation and inactivation by liver. Further, the present findings suggest the potential of curcumin for modification of gastric and intestinal carcinogenesis initiated with NOC.
为阐明姜黄素抑制NMBA诱导的食管癌发生的潜在机制，我们分别通过免疫印迹分析和艾姆斯预孵育试验评估了环境致癌物的CYP水平和诱变激活，以及用姜黄素和/或NMBA处理的F344大鼠的胆红素、4-硝基苯酚和睾酮UDPGT活性。皮下注射0.5 mg/kg NMBA 5周和/或喂食0.05%和0.2%姜黄素6周，对组成型CYP蛋白的肝脏水平、肝脏S9的诱变激活或肝脏UDPGT活性均无显著影响。相比之下，与载体对照相比，灌胃0.2%姜黄素可使食管CYP2B1和2E1降低多达60%。同样，用270 mg/kg姜黄素进行胃内治疗可降低食管和胃中的CYP2B1和CYP2E1，但对肺、肾或肠道无影响。相反，处理组大鼠的大肠CYP2B1比对照组高2.8倍。在处理组大鼠中，在食管和胃S9存在的情况下，包括NMBA在内的NOC的诱变活性显著降低，而在大肠S9存在的情况下，诱变活性比对照高2.2 - 3.0倍。这些结果表明，姜黄素对食管癌发生的调节作用可归因于在起始阶段食管CYP2B1对NMBA代谢激活的降低，而肝脏的代谢激活和失活没有作用。此外，目前的研究结果表明姜黄素对由NOC引发的胃癌和肠癌发生具有调节潜力。
